The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells

Pont, Lotte M. E. Berghauser; Spoor, Jochem K. H.; Venkatesan, S.; Swagemakers, Sigrid; Kloezeman, Jenneke J.; Dirven, Clemens; Spek, Peter J. van der; Lamfers, Martine L.M.; Leenstra, Sieger

doi:10.18632/genesandcancer.42

Cited by 34 publications

(26 citation statements)

References 43 publications

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“…[ 20 ]The mRNA of the parental glioblastoma tissue of the GSCs was isolated with the RNeasy Mini kit (#74104, Qiagen Inc., CA, USA) The expression levels were analyzed by the HumanHT-12 v4 Expression BeadChip microarray (Illumina, CA, USA), as we have described previously. [ 21 ] The normalization and batch effect removal was done as described previously by using Partek software, version 6.6 (Partek Inc., St. Louis, MO, USA). The expression data was used to subtype the tumors to the transcriptionally-defined glioblastoma classification of the TCGA.…”

Section: Methodsmentioning

confidence: 99%

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells

et al. 2015

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BackgroundA phase I/II trial for glioblastoma with the oncolytic adenovirus Delta24-RGD was recently completed. Delta24-RGD conditionally replicates in cells with a disrupted retinoblastoma-pathway and enters cells via αvβ3/5 integrins. Glioblastomas are differentially sensitive to Delta24-RGD. HDAC inhibitors (HDACi) affect integrins and share common cell death pathways with Delta24-RGD. We studied the combination treatment effects of HDACi and Delta24-RGD in patient-derived glioblastoma stem-like cells (GSC), and we determined the most effective HDACi.MethodsSAHA, Valproic Acid, Scriptaid, MS275 and LBH589 were combined with Delta24-RGD in fourteen distinct GSCs. Synergy was determined by Chou Talalay method. Viral infection and replication were assessed using luciferase and GFP encoding vectors and hexon-titration assays. Coxsackie adenovirus receptor and αvβ3 integrin levels were determined by flow cytometry. Oncolysis and mechanisms of cell death were studied by viability, caspase-3/7, LDH and LC3B/p62, phospho-p70S6K. Toxicity was studied on normal human astrocytes. MGMT promotor methylation status, TCGA classification, Rb-pathway and integrin gene expression levels were assessed as markers of responsiveness.ResultsScriptaid and LBH589 acted synergistically with Delta24-RGD in approximately 50% of the GSCs. Both drugs moderately increased αvβ3 integrin levels and viral infection in responding but not in non-responding GSCs. LBH589 moderately increased late viral gene expression, however, virus titration revealed diminished viral progeny production by both HDACi, Scriptaid augmented caspase-3/7 activity, LC3B conversion, p62 and phospho-p70S6K consumption, as well as LDH levels. LBH589 increased LDH and phospho-p70S6K consumption. Responsiveness correlated with expression of various Rb-pathway genes and integrins. Combination treatments induced limited toxicity to human astrocytes.ConclusionLBH589 and Scriptaid combined with Delta24-RGD revealed synergistic anti-tumor activity in a subset of GSCs. Both HDACi moderately augmented viral infection and late gene expression, but slightly reduced progeny production. The drugs differentially activated multiple cell death pathways. The limited toxicity on astrocytes supports further evaluation of the proposed combination therapies.

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Section: Methodsmentioning

confidence: 99%

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells

et al. 2015

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“…The results have been mostly disappointing, since increased toxicity with cetuximab was not accompanied by improved overall survival compared to standard therapy. Thus cetuximab in combination with radiation has only received FDA approval for the treatment of locally advanced head and neck cancer [ 93 ]. Next generation EGFR inhibitors must prove a better toxicity profile and increased radiosensitivity.…”

Section: Targets For Radiosensitizationmentioning

confidence: 99%

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Maier

Hartmann

Wenz

et al. 2016

IJMS

330

259

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During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

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“…Obatoclax, a pan-Bcl-2 inhibitor with promising efficacy, was recently shown by Berghauser et al 99 to overcome apoptosis resistance to the histone deacetylase inhibitors SAHA and LBH589, and to act as a radiosensitizer in patient-derived GSCs. Obatoclax had a synergistic effect with SAHA and LBH589 and sensitizes cells to HDACi/radiation therapy (RTx).…”

Section: Drugs Known To Increase Apoptosis In Cancer Stem Cellsmentioning

confidence: 99%

“…The authors found that the gene predictive for treatment response is the F-box/WD repeat-containing protein-7, which is related to Bcl-2 inhibition and HDACi sensitivity. 99 …”

Section: Drugs Known To Increase Apoptosis In Cancer Stem Cellsmentioning

confidence: 99%

Resistance to Cell Death and Its Modulation in Cancer Stem Cells

2016

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Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs. Several signaling pathways—including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin—and expression of the CSC markers CD133, CD24, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain CSC properties. Studying such pathways may help to understand CSC biology and lead to the development of potential therapeutic interventions to render CSCs more sensitive to cell death triggered by chemotherapy and radiation therapy. Moreover, recent demonstrations of dedifferentiation of differentiated cancer cells into CSC-like cells have created significant complexity in the CSCs hypothesis. Therefore, any successful therapeutic agent or combination of drugs for cancer therapy must eliminate not only CSCs but differentiated cancer cells and the entire bulk of tumor cells. This review article expands on the CSC hypothesis and paradigm with respect to major signaling pathways and effectors that regulate CSC apoptosis resistance. Moreover, selective CSC apoptotic modulators and their therapeutic potential for making tumors more responsive to therapy are discussed. The use of novel therapies, including small-molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of CSCs, immunotherapy, and noncoding microRNAs may provide better means of treating CSCs.

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The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells

Cited by 34 publications

References 43 publications

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Resistance to Cell Death and Its Modulation in Cancer Stem Cells

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